The present invention relates to the general field of rapid prototyping technology, and in particular, to stereolithography methods and systems.
Rapid prototyping (RP) technologies, also known as Solid Freeform Fabrication (SFF), layered manufacturing and other similar technologies enable the manufacture of complex three-dimensional (3D) parts. RP technologies, in particular, generally construct parts by building one layer at a time. RP technologies are commonly used to build parts and prototypes for use in, for example, the toy, automotive, aircraft and medical industries. Oftentimes prototypes made by RP technologies aid in research and development and provide a low cost alternative to traditional prototyping. In a few cases, RP technologies have been used in medical applications such as those associated with reconstructive surgery and tissue engineering (TE).
Stereolithography (SL) is one of the most widely used RP technologies known in the art. The resolution of SL machines and the ability of SL to manufacture highly complex 3D objects, make SL ideal for building both functional and non-functional prototypes. In particular, SL techniques provide an economical, physical model of objects quickly and prior to making more expensive finished parts. The models are readily customizable and changes may be easily implemented.
SL generally involves a multi-stage process. For example, the first stage involves designing and inputting a precise mathematical geometric description of the desired structure's shape into one of many computer-aided design (CAD) programs and saving the description in the standard transform language (STL) file format. In the second stage, the STL file is imported into SL machine-specific software (RP software). The RP software slices the design into layers and determines the placement of support structures to hold each cross-section in place while building the structure layer by layer. By computing build parameters, the RP software controls the part's fabrication. In the layer preparation stage, the build parameters for the desired part are translated into machine language. Finally, the machine language controls the SL machine to build a desired part and its support structure layer by layer. SL machines typically focus an ultraviolet (UV) laser onto a cross-section of a liquid photopolymer resin. The laser, in turn, selectively cures a resin to form a structure, such as anatomical shapes (i.e., organs and tissues), layer by layer. Ultimately, the part is cleaned, the support structure is removed and the part is post-cured (typically exposed to UV) prior to completion. The operator may, however, need to sand, file or use some other finishing technique on the part in order to provide a specific surface finish to the structure, which may include painting, plating and/or coating the structure's surface.
SL technologies known in the art generally include, for example, a laser, a liquid level sensing system, laser beam optics and controllable scanning mirror system, a vertically movable platform, a single resin retaining receptacle or vat and a recoating device. During the laser scanning phase, a series of optics and controllable scanning mirrors typically raster a UV laser beam to solidify a photocurable polymer resin. The subject 3D part is first attached to the platform by building a support structure with the platform in its topmost position. This step allows for misalignment between the platform and the surface of the liquid resin—once constructed, the base support structure is parallel with the surface of the liquid. When building the subject part simultaneously with its required support structure and after the laser beam completes a layer, the platform typically is vertically traversed downward a distance equal to the build layer thickness. After the platform is vertically traversed downward and prior to selectively curing the next layer, a recoating device is typically traversed horizontally across the part leaving a uniform layer of liquid polymer. The recoating device ensures that trapped spaces within the part are filled with liquid resin (which may be required for future build layers) and maintains a constant build layer thickness. The process repeats as each layer is built. Complex-shaped parts are thus manufactured by repeating the layering process. Once complete, the part is typically raised out of the liquid resin, the support structure is removed from the part, the part is cleaned and then post-cured. The operator may, however, need to sand, file or use some other finishing technique on the part in order to provide a specific surface finish to the structure, which may include painting, plating and/or coating the structure's surface.
Certain RP technologies facilitate the fabrication of parts used in medical applications. Such parts require additional design considerations. TE techniques, in particular, rely on the use of a scaffold, a framework that provides structural support for cells while those cells regenerate the tissue. These scaffolds may also provide signals to the cells to elicit particular desired behaviors. One of the most challenging problems in TE is providing adequate nutrition to cells seeded within implanted scaffolds. TE techniques known in the art have shown that the diffusion of oxygen and nutrients is not sufficient to sustain cell viability beyond distances of approximately 75 microns in the body. Accordingly, TE techniques must retain precise control over the resulting 3D geometry in order to design favorable diffusion into a scaffold and thus maintain cell viability. Although SL has the resolution and speed to make highly complex 3D structures economically, SL has not been used to aid in TE because SL resins known in the art are not certified for implantation in humans. Other systems known in the art for creating complex 3D TE scaffolds are time-consuming and complicated and therefore are not conducive to mass manufacturing. Accordingly, what is desired is a system and method of quickly building and mass producing biocompatible and implantable constructs with precise control over placement of scaffold materials and bioactive agents and cells to promote favorable tissue regeneration and nutrient diffusion within a scaffold in an economical manner possibly with SL technologies.
Hydrogels are currently being used for a number of different TE applications, particularly for soft tissues. Hydrogels are biocompatible materials with high water content and are suitable as scaffolding materials because of their similarity, both mechanically and structurally, to extracellular matrices. In addition, hydrogels exhibit favorable diffusion characteristics and are currently used in photolithographic processes using manual lithographic masking techniques as well as a variety of other processes. There are enumerable TE applications that can benefit from precisely manufacturing hydrogel constructs with bioactive agents and cells. Hydrogels, however, are not currently adequately supported by layered manufacturing (LM) technologies using SL.
Embedded channels may be important to build angiogenic structures or roadways between proliferative structures located within hydrogel scaffolds. Thus, biological and architectural cues need to be assessed to fabricate cytocompatible scaffolds. For example, gradients of growth factors have been found to direct cell migration and neurite extension, and ultimately enhance tissue regeneration in both guided angiogenesis and subsequent vasculogenesis in vivo and peripheral nerve regeneration. Several agents, such as vascular endothelial growth factor (VEGF), for example, exert potent angiogenic effects. In the case of VEGF, these effects are several-fold, ranging from marrow stimulation of endothelial precursor production and release to local selective recruitment of precursors and enhanced, for example, vascular permeability which in turn enhances vascular bud formation.
Once initiated, a vascular bud is potentially guided by gradients that allow permeability in the target bud direction and stabilization of the adjacent sides. Several stabilizing agents have been identified in vitro. These agents, such as angiopoietin 2, serve to prevent aberrant budding and to guide the bud in the direction of high permeability. When provided nonspecifically, these agents suppress bud formation. Thus, a gradient in VEGF will facilitate guided bud formation and propagation. A reverse gradient of angiopoietin 2 should stabilize directional control of angiogenesis and prevent nonspecific turns or termination. Further, extracellular matrix (ECM) elements have been shown to either facilitate (hyaluronic acid) or inhibit (polymerized collagen) directional angiogenesis through specific cellular receptors. Thus, what is desired is exogenously engineered gradients of biologic agents and/or ECM that will potentially facilitate induction and directional propagation of angiogenesis in an engineered implantable, cytocompatible scaffold.
One particular need in the art is a system and method to create complex nerve guidance conduits. Currently, peripheral nerve repair is accomplished by using a nerve autograft. Autografting involves taking a portion of a nerve from one location in the body (a donor site) and placing it in another part of the body exhibiting a specified need. There are several drawbacks to autografting including, for example, requiring multiple surgical sites and a considerable risk of neuroma formation at the donor site. Oftentimes, results from autografting have been variable and more often altogether unsuccessful.
Nerve guidance conduits (NGCs) offer a promising alternative to autografting. NGCs are tubes that are sutured to nerve stumps to bridge the gap and aid in guiding sprouting axons from the regenerating nerve toward their target. NGCs retain neurotrophic factors and other compounds secreted by the damaged nerve, thus aiding in regeneration and preventing the infiltration of fibrous tissue. There are currently two types of NGCs available, one made of collagen and the other made of polyvinylalcohol (a hydrogel). These NGCs, however, are simple, single material and single lumen conduits that fail to recreate the 3D structure of the nerve.
Multi-lumen conduits are desirable because they mimic the natural peripheral nerve structure and increase surface area for neurite attachment/extension and support cell attachment/migration. Multi-lumen conduits thus allow for more precisely located growth factors and support cells within a tissue scaffold. Although multi-lumen conduits made with poly(lactic-co-glycolic acid) have previously been made, the techniques used to make such scaffolds are difficult to scale-up to a manufacturing level, do not allow for cells to be homogeneously seeded within the conduit during its manufacture, and do not allow the mechanical properties of and bioagents within the construct to vary throughout the construct, which is afforded by layered manufacturing.
Thus, systems known in the art fail to mass produce complex, multiple material 3D constructs with embedded channel architecture from hydrogels using SL technology. Accordingly, what is desired is a low cost, efficient and easy-to-use system which has the ability to fabricate hydrogel constructs with embedded channels of virtually any orientation. What is further desired is a system which enables scaffold fabrication with internal channel architecture including any variable channel orientation. What is still further desired is the ability to fabricate multiple material hydrogel constructs that enable the construction of precise scaffolds with variable hydrogel scaffold materials both within and across layers.
In addition, what is still desired is the ability to fabricate multiple material hydrogel constructs with precisely placed bioactive agents and cells both within and across layers. What is further desired is a simple method for manufacturing multi-lumen conduits of bioactive hydrogels as potential scaffolds for peripheral nerve regeneration. What is still further desired is a simple method for manufacturing complex bioactive hydrogel constructs as potential scaffolds for guided angiogenesis and adipose tissue generation. What is also still further desired is a simple method for fabricating multi-material constructs that may serve as TE scaffolds.